SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes
Jennifer A. Schaub, … , Matthias Kretzler, Petter Bjornstad
Jennifer A. Schaub, … , Matthias Kretzler, Petter Bjornstad
Published January 13, 2023
Citation Information: J Clin Invest. 2023;133(5):e164486. https://doi.org/10.1172/JCI164486.
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Research Article Metabolism Nephrology

SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

Abstract

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[–]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(–) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.

Authors

Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. Hodgin, Frank C. Brosius III, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad

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Figure 4

Suppression of central metabolic pathways with SGLT2 inhibition in PT.

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Suppression of central metabolic pathways with SGLT2 inhibition in PT. (...
(A) Enrichment analysis using Reactome data of suppressed transcripts with SGLT2 inhibition showing metabolism has greatest number of altered transcripts (n > 200). (B) Pathway enrichment analysis using Reactome database of enhanced transcripts with SGLT2 inhibition. A pathway was considered significant if its P value was less than 0.05 and included at least 5 transcripts reversed by SGLT2i. (C) Bar plots showing transcript-level alterations (log2FC) when comparing T2Di(–) to HCs (pink) and T2Di(+) to T2Di(–) (blue). (D) Schematic summarizing the transcriptional changes in PT cells. SGLT2i impairs uptake of sodium and glucose into PT cells via SLC5A2, leading to decreased expression of glycolytic and TCA cycle transcripts. Decreased glucose uptake and glycolysis may decrease mTORC1 activity.